2 Undergraduate medical student, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Abstract

Objective:

To review the literature on current applications of corneal Collagen Cross-Linking (CXL).

Methods:

A review of publications on corneal cross-linking was conducted. This included systemic reviews, randomized controlled clinical trials, cohort studies, case-controlled studies and case series. A summary of the publications is tabulated.

Results:

The original indication of riboflavin – Ultraviolet-A (UVA) induced corneal collagen cross-linking is to arrest the progression of keratoconus. Studies show that it is effective in arresting the progression of keratoconus and post-LASIK ectasia with the standard Dresden protocol (epithelium-off). There are also improvements in visual, keratometric and topographic measurements over time. Severe complications of cross-linking are rare. The epithelium-on techniques have less efficacy than the Dresden protocol. Accelerated protocols have variable results, with some studies reporting comparable outcomes to the Dresden protocol while other studies reporting less efficacious outcomes. Cross-linking combined with refractive procedures provide better visual outcome but long term studies are warranted. Cross-linking for the treatment of infective keratitis is a promising new treatment modality. Initial studies show that it is more effective for superficial rather than deep infections and for bacterial rather than fungal infections.

Conclusions:

Corneal cross-linking is a procedure with an expanding list of indications from the treatment of corneal ectasias to infective keratitis. While the standard Dresden protocol is established as the gold standard treatment for progressive keratoconus, the more recent protocols may require further refinements, investigative and long-term studies.

Unique Statistics:

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

1. INTRODUCTION

Wollensak, Spoerl and Seiler reported the first clinical study on riboflavin – UVA induced corneal collagen cross-linking procedure for the treatment of progressive keratoconus in adults [1Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135(5): 620-7.[http://dx.doi.org/10.1016/S0002-9394(02)02220-1] [PMID: 12719068] ]. Since then, corneal cross-linking has been widely used for the treatment of progressive keratoconus as well as other conditions including post-LASIK ectasia. Corneal cross-linking is also used in conjunction with laser vision correction procedures and intrastromal ring procedures. More recently, it is used to treat infective keratitis. The purpose of this paper is to provide a review of the current trends in practice applications of corneal collagen cross-linking.

The cross-linking procedure is performed under topical anesthesia (eg tetracaine 1%). An epithelial debridement (8-9mm) is performed followed by instillation of riboflavin 0.1% eyedrops for 30 minutes at 2 minute intervals. The riboflavin solution may contain 20% dextran as in the earlier studies [1Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135(5): 620-7.[http://dx.doi.org/10.1016/S0002-9394(02)02220-1] [PMID: 12719068] ] or may be dextran free containing hydroxypropyl methylcellulose [6Jain V, Gazali Z, Bidayi R. Isotonic riboflavin and HPMC with accelerated cross-linking protocol. Cornea 2014; 33(9): 910-3.[http://dx.doi.org/10.1097/ICO.0000000000000188] [PMID: 25014154] ]. The dextran-free riboflavin preparation may reduce the incidence of stromal dehydration during the procedure. At the end of the riboflavin instillation, ultrasound pachymetry is performed at the centre of the cornea and if the corneal thickness is below 400um, hypotonic riboflavin eyedrops are applied until the corneal thickness returns to a minimum of 400 um thickness. The cornea is then irradiated with the Ultraviolet A (UVA) device at 3mW/cm2 for 30 minutes with continued instillation of riboflavin eyedrops at 2-minute intervals. After irradiation is completed, topical antibiotics/steroids and bandage lens are applied.

The standard Dresden protocol (epithelium-off) corneal cross-linking is associated with significant postoperative pain and visual recovery is gradual. There are also risks of infection and corneal scarring. Hence, epithelium-on corneal cross-linking was introduced to reduce the issues associated with the standard protocol. However, riboflavin is a hydrophilic molecule making penetration through the intact hydrophobic corneal epithelium difficult. In order to improve epithelial permeability to riboflavin, additives such as benzalkonium chloride, topical aneasthetic, tris-hydroxymethyl aminomethane (trometamol), sodium ethylenediaminetetraacetic acid (EDTA) are included in the riboflavin. Other techniques include increased riboflavin concentration and iontophoresis.

The Bunsen-Roscoe Law of Reciprocity states that the photochemical biological effect of ultraviolet light is proportional to the total energy dose delivered, regardless of the applied irradiance and time [49Bunsen RRH. Photochemische Untersuchungen Poggendorff’s Annalen 1855; 96: 373-94.]. In the context of UVA cross-linking, for the same energy dose delivered, one could shorten the duration of treatment by applying a higher irradiance power. Laboratory studies show that this law could be applied for corneal cross-linking. Wernli et al treated ex vivo porcine eyes with CXL using a total of 5.4J/cm2 delivered in a range of irradiances from 3 to 90mW/cm2. Significant stiffening was observed in eyes treated with irradiances from 3 to 45mW/cm2 [50Wernli J, Schumacher S, Spoerl E, Mrochen M. The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Invest Ophthalmol Vis Sci 2013; 54(2): 1176-80.[http://dx.doi.org/10.1167/iovs.12-11409] [PMID: 23299484] ].

Shetty et al reported a comparative study of CXL and accelerated CXL in 138 eyes of 138 patients with 1 year follow-up [56Shetty R, Pahuja NK, Nuijts RM, et al. Current protocols of corneal collagen cross-linking: Visual, refractive, and tomographic outcomes. Am J Ophthalmol 2015; 160(2): 243-9.[http://dx.doi.org/10.1016/j.ajo.2015.05.019] [PMID: 26008626] ]. He reported that the accelerated CXL (9mW/cm2 for 10 minutes and 18mW/cm2 for 5 minutes) had similar outcomes to standard CXL but the accelerated CXL using 30mW/cm2 for 3 minutes was not as efficacious.

The reduced efficacy of the 30mW/cm2 treatment is postulated to be due to the depletion of oxygen in these high fluence treatments and pulsed treatments were introduced in an effort to replenish oxygen in the cornea during high fluence treatments. Mazotta et al [57Mazzotta C, Traversi C, Paradiso AL, Latronico ME, Rechichi M. Pulsed light accelerated crosslinking versus continuous light accelerated crosslinking: One-Year results. J Ophthalmol 2014; 2014: 604731.[http://dx.doi.org/10.1155/2014/604731] [PMID: 25165576] ] reported a greater reduction of keratometry in pulsed compared to continuous treatment

The treatment protocol of accelerated CXL is still in evolution due to the variability of the outcomes reported. Further long term studies are needed to confirm the comparability of accelerated CXL to CXL.

Although CXL is effective in stabilizing keratoconus, in many cases, patients are unable to achieve functional vision after CXL and still require rigid contact lens wear. Hence refractive treatments in combination with CXL (CXL plus) have been introduced to provide patients with better visual acuity.

LASIK, with the creation of a corneal flap and ablation of corneal tissue weakens the biomechanical strength of the cornea and in susceptible eyes, may predispose to post-LASIK ectasia. In order to strengthen the cornea, accelerated corneal cross-linking is performed simultaneously after the LASIK procedure. Studies have reported that combined laser in-situ Keratomileusis (LASIK) and accelerated corneal cross-linking may confer additional benefits of early refractive and keratometric stability after LASIK, improving the predictability of refractive outcomes in patients. The indications are high myopia corrections, hyperopic corrections, patients with lower residual stromal bed thickness and patients with thin corneas.

One of the goals of performing LASIK with accelerated CXL is reducing the risk of post-LASIK ectasia. A review of the literature of eyes that had undergone LASIK and accelerated cross-linking with at least 2 years follow-up showed no report of post-LASIK ectasia supporting the claim that LASIK with accelerated CXL may prevent post-LASIK ectasia [110Tomita M. Combined laser in-situ keratomileusis and accelerated corneal cross-linking: an update. Curr Opin Ophthalmol 2016; 27(4): 304-10.[http://dx.doi.org/10.1097/ICU.0000000000000281] [PMID: 27152484] ]. However, post-LASIK ectasia has been shown to develop as long as 5 to 10 years postoperatively. Hence these reports are not sufficient to make this conclusion and further long term studies are warranted.

Crosslinked corneal tissue has been shown to have stiffer biomechanical properties and to be more resistant to degradation by collagenolytic enzymes. Robert et al reported on cross-linking of the Boston keratoprosthesis donor carrier to prevent corneal melting in a patient with post KPro corneal melt. The patient maintained his visual acuity and showed no evidence of corneal thinning or melt in the first postoperative year [141Robert MC, Arafat SN, Ciolino JB. Collagen cross-linking of the Boston keratoprosthesis donor carrier to prevent corneal melting in high-risk patients. Eye Contact Lens 2014; 40(6): 376-81.[http://dx.doi.org/10.1097/ICL.0000000000000081] [PMID: 25320957] ].

CONCLUSION

Corneal cross-linking is a unique procedure with an expanding list of indications from the treatment of corneal ectasia to infective keratitis. While the standard Dresden protocol is established as the gold standard treatment for progressive keratoconus, the more recent protocols may require further refinements, investigations and long-term studies. New indications and treatment protocols are also being developed and we look forward to these treatments in the future.

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